of nevirapine with cotrimoxazole prophylaxis in HIV-exposed uninfected infants
(HIV-EU) until six months of age in Zimbabwe
was safe with no immediate or long-term adverse effects, researchers on behalf
of the HIV Prevention Trials Network (HPTN) 046 protocol trial report in the
advance online edition of AIDS.
findings from this secondary data analysis have important policy implications
for HIV-exposed but uninfected infants in resource-poor settings.
HPTN 046 protocol, a prospective randomised placebo controlled trial, looked at
the safety and efficacy of nevirapine prophylaxis against HIV transmission in
breast milk with infants followed for 18 months.
makers can now make informed decision regarding the WHO 2010 prevention of
mother-to-child (PMTCT) guidelines and the combined use of nevirapine and
cotrimoxazole prophylaxis for extended periods of time. Such use is critical in
these settings where frequent monitoring is challenging, and where the
difficulties of travelling long distances and the high costs of transportation
make regular clinic visits difficult.
guidelines are based on evidence of the effectiveness of the extended use of
daily nevirapine in reducing breast milk transmission of HIV. Daily use of nevirapine
prophylaxis in HIV-exposed but uninfected infants for PMTCT from birth until
one year of age, or until the stopping of breastfeeding (whichever comes first),
World Health Organization also recommends that HIV-exposed but uninfected
infants get cotrimoxazole (CTX) prophylaxis from the age of 4-6 weeks until
they are no longer exposed to HIV and have confirmation of being HIV negative.
Cotrimoxazole is a highly effective antibiotic against pneumonia and other
effects with the extended use of nevirapine have included some reports of rash
and a decrease in white blood cells (neutropenia); these side effects in
addition to anaemia are frequently seen with the use of CTX.
the safety of the combined used in HIV-EU is not well understood. The authors
note that there are no studies assessing the risks in HIV-EU infants and that
safety data is based on HIV-infected individuals, notably adults. Without such
data effective public health implementation is handicapped.
the authors chose to determine the risk and severity of neutropenia and/or
anaemia and severe rash in HIV-EU infants randomised to one of two study arms:
six months of getting daily nevirapine and cotrimoxazole prophylaxis from six
weeks until breastfeeding stopped compared to those getting cotrimoxazole
the release in August 2007 of the Six Week Extended Nevirapine (SWEN) trial
that showed a 50% reduction in MTCT through breast milk recruitment into
HPTN-043 stopped. Analysis was based on a fixed sample size of infants enrolled
between February and August 2007.
the 293 mother-infant pairs randomised incidence of neutropenia and/or anaemia
and skin rash, regardless of the study arm, was highest during the first six
weeks of life then from six weeks to six months and lowest in the six to 12
(96%) infants had at least one episode of neutropenia and/or anaemia and about
half had the most severe form with relatively few (13%) experiencing skin rash.
The authors suggest this may reflect a high background of neutropenia and/or
anaemia in this study population. Or, it may reflect an overestimation bias
since the ranges used to determine potential toxicity in what is a primarily
black-African population are white-based norms.
six weeks the time to any adverse event was similar in both arms for
neutropenia and/or anaemia (all grades); for neutropenia and/or anaemia (grade
3 or above); and skin rash (grade 2 or above: HR, 95% CI: 1.26 (0.96-1.66);
1.27 (0.80-2.03); and 1.16 (0.46-2.90), respectively.
adverse event in this trial was defined as “any unfavourable or unintended
symptom, sign (including an abnormal laboratory finding) or disease temporally
associated with the use of the study product (onset after enrolment),
regardless of relatedness.”
were no statistically significant differences in the immediate (six weeks to
six months) or long-term (six-12 months) adverse event risks among infants on
nevirapine and cotrimoxazole compared to those on cotrimoxazole alone.
authors note the potential for drug-drug interactions resulting in increased
risk of patient illness and death are well documented; taking nevirapine may
alter the amount of other drugs absorbed into the blood stream and vice versa.
authors note that the placebo design of this trial within a setting with
routine cotrimoxazole prophylaxis “provided a unique opportunity to assess the
immediate and long term adverse events risk associated with concurrent
nevirapine and CTX use.”
to eliminate potential confounders (variables such as infants who got
zidovudine tail and maternal ARVs found in breastmilk) were made in the time to
adverse event and adverse event risk assessments.
authors conclude that “extended
nevirapine and cotrimoxazole prophylaxis until six months of age among HIV-EU
did not appear to increase the immediate or long-term risk of neutropenia,
anaemia or skin-rash. However, the safety of concurrent use beyond six months,
among HIV-EU breastfed infants, as is currently recommended by WHO needs